Monochromatic infrared light energy (MIRE) therapy is controversial. Do you prescribe this therapy? How can infrared light reverse sensory neuropathy or heal ulcers? Some reports indicate that just two weeks of therapy is enough to show significant improvement. Some patients rave about its benefits. Patients may say they no longer have numbness and/or pain. They may say they sleep better. It sounds too good to be true. Aside from the anecdotal claims, here are just a handful of published studies that have been used to evaluate MIRE therapy to improve sensory neuropathy, painful neuropathy and wound healing. There are four retrospective, two prospective cohort studies and three randomized clinical trials that have evaluated the effect of this therapy on peripheral sensory neuropathy among people with diabetes.1-9 However, a closer review of these studies reveals that bias, limitations in study design and errors in statistical analysis have lead to important errors in the interpretation of the study data and the authors’ conclusions. The three randomized clinical trials (RCTs) that evaluate changes in diabetic sensory neuropathy with active and sham monochromatic infrared light therapy offer the highest level of clinical evidence currently available. All three of these trials randomize one extremity to receive active therapy and one extremity to receive sham therapy. The study authors evaluate people with diabetes with various levels of sensory neuropathy. Semmes-Weinstein monofilaments (SWM) are the primary tool the researchers used to evaluate neuropathy in all three studies although they utilized other objective and subjective tools as well. The clinical trials by Leonard and Arnall report statistically significant improvement in limbs treated with active MIRE therapy based on “changes” in Semmes-Weinstein monofilament testing.7,8 However, Clifft and colleagues did not identify any improvement after therapy in any of the test parameters.9 When it comes to research, clinicians tend to be the least comfortable with statistical analysis so we tend to believe what we are told. However, statistical analysis and design issues are often the crux of critical appraisal. Several of the fatal flaws in the published MIRE clinical trials involve errors in analysis. Some of the basic analytic errors in Leonard and Arnall’s trials contributed to misinterpretation of the data and reporting the wrong conclusion.7,8 In these studies, researchers used inappropriate statistical tests and they failed to compare active and sham treatment results at the end of both studies. Leonard’s study did not use an “intent to treat” analysis.7
What About The Flaws In Study Design And Analysis?
One of the most interesting aspects of the studies that evaluate MIRE is the consistent and often large placebo effect. There is an improvement in SWM testing in the sham group in all three randomized clinical trials. The strong placebo effect is probably the reason the uncontrolled retrospective and prospective studies had positive results.1-6 In Leonard’s study, there is such a strong placebo effect that when one compares pre- and post- intragroup comparisons, the Michigan Neuropathy Screening Questionnaire shows a significant change in active and sham treatment groups.7 Arnall’s study reports as much as a 70 percent improvement in SWM results in the sham treatment group.8 Both Leonard and Arnall only compared pre- and post-therapy results within the active or within the sham groups.7,8 There was no analysis that compared outcomes between treatment groups. Since there was such a large placebo effect in the sham treatment group, there is not a significant difference between active and sham therapy at the end of the studies. For instance, in the Leonard study, researchers correctly identified 2.4 out of five SWM sites in the active group and 3.0 out of five sites in the sham group.7 Clifft and colleagues provide the only report that compares outcomes between sham and active treatment groups.9 Clifft did not identify any significant difference between MIRE treatment and sham treatment. Intent to treat (ITT) is a basic tenet of evaluating data from clinical trials. Essentially, ITT dictates that researchers include every patient who is randomized into a study in the analysis. It stops investigators from eliminating those who did not get a good result, were not compliant or had a negative response for some other reason. Leonard, et al., did not provide an analysis of the entire study population. They separately reported outcomes and provided analysis for patients with severe neuropathy and less severe neuropathy.7 The group with severe neuropathy did not benefit from MIRE therapy. Leonard’s results primarily focused on patients with less severe neuropathy or patients who could feel the 300 g SWM. Monochromatic infrared light energy did not have any benefit among people with severe neuropathy. This seems like a very odd way to dichotomize the study population. There is a very wide range among patients who can feel between 10 and 300 g of force.
Questioning The Use Of The SWM
The main tool used to evaluate changes in sensory neuropathy in all three randomized, controlled trials was some form of the SWM. While many papers tout the SWM as good screening tool for neuropathy with loss of protective sensation, the inaccuracy and inconsistency of SWMs and changes in the instrument’s loading force over time make it a poor choice for clinical research.5-9 Yong, Booth and McGill described inaccuracy and variability of new SWM and changes in the loading force of instruments with repetitive use.10-12 The “pivotal” studies to evaluate MIRE therapy have relied on a flawed and usually inaccurate tool to test neuropathy. Vibration perception threshold (VPT) testing is a test that is recommended for use in longitudinal studies. Arnall’s paper was the only one that used VPT testing as part of the clinical evaluation of sensory neuropathy. Although no data was cited, there was not a significant change in VPT, according to Arnall. Leonard reported “statistically significant” improvement in sensory neuropathy in limbs that received MIRE therapy.7 However, even if the statistical analysis the researchers used in the study was correct, the statistically significant results do not seem like they are clinically meaningful. For instance, at the end of Leonard’s study, in the MIRE treatment group, researchers accurately identified an average 2.4 sites out of five sites tested with the SWM.7 Clinically, “loss of protective sensation” is often defined as one or two sites missed with the 10 g monofilament.10 Accordingly, the level of improvement still leaves the patient with “loss of protective sensation.” The authors did not report the proportion of patients who changed from having a “high-risk foot” to having a normal level of sensation. That type of information would be more meaningful to most clinicians. Arnall, on the other hand, reports that patients in both treatment arms had an improvement in peripheral sensation so the average SWM values were <10 g of force.8 Could MIRE have a systemic effect? All three randomized clinical trials randomized limbs as opposed to randomizing patients. This design could allow for a systemic effect so both extremities could have benefited from therapy which was provided to one limb. This might explain the large and unexpected placebo effect that occurred in all three clinical studies.
Monochromatic infrared light energy therapy is a multimillion-dollar industry. If this is a therapy that really works, we need to provide it aggressively for all of our patients with diabetes who are “at risk” for foot ulceration. However, if the therapy does not work, we need to make sure healthcare resources are not wasted. We are the gatekeepers in many respects and prescribing expensive therapy that is ineffective or, at best, unproven is not a benefit to the patient or our profession. At first glance, the literature appears to support the use of MIRE to improve peripheral neuropathy among patients with diabetes. However, there are a number of concerns about the existing science. The quality of the clinical data is suspect and the ability of therapy to “reverse neuropathy” and prevent foot complications (such as ulceration, infection and amputation) related to sensory neuropathy is unproven. Further research needs to address design and analysis concerns. Dr. Lavery (shown at the right) is a Professor in the Department of Surgery at Texas A&M Health Science Center College of Medicine. Dr. Steinberg (shown at the left) is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Editor’s note: For further reading, see “Current And Emerging Options For Treating Diabetic Neuropathy” in the March 2005 issue of Podiatry Today.
References 1. Harkless LB, Delellis, Carnegie DH, Burke TJ. Improved foot sensitivity and pain reduction in patients with peripheral neuropathy after treatment with monochromatic infrared photo energy. J Diabetes Compl 20(2006) 81-87. 2. Powell MW, Carnegie DE, Burke TJ. Reversal of diabetic neuropathy and new wound incidence: the role of MIRE. Adv Skin Wound Care 17:295-300, 2004. 3. Powell MW, Carnegie DE, Burke TJ. Reversal of diabetic neuropathy and new wound incidence: the role of MIRE. Adv Skin Wound Care 17:295-300, 2004. 4. DeLellis SL, Carnegie DH Burke TJ. Improvement of sensitivity in patients with peripheral sensory neuropathy. J Am Podiatr Med Assoc 95: 143-147, 2005. 5. Prendergrast JJ, Miranda G, Sanchez M. Improvement sensory impairment in patients with peripheral sensory neuropathy. Endocr Prac 10: 24-30, 2004. 6. Kochman AB, Carnegie DH, Burke TJ. Symptomatic reversal of peripheral neuropathy in patients with diabetes. J Am Podiatr Med Assoc, 2002. 92(3):125-30. 7. Leonard DR, Farooqi MH, Myers S. Restoration of sensation, reduced pain, and improved balance in subjects with diabetic peripheral neuropathy: a double-blind, randomized, placebo-controlled study with monochromatic near-infrared treatment. Diabetes Care, 2004. 27(1):168-72. 8. Arnall DA, et al. The restorative effects of pulsed infrared light therapy on significant loss of peripheral protective sensation in patients with long-term type 1 and type 2 diabetes mellitus. Acta Diabetol, 2006. 43(1):26-33. 9. Clifft JK, et al. The effect of monochromatic infrared energy on sensation in patients with diabetic peripheral neuropathy: a double-blind, placebo-controlled study. Diabetes Care, 2005. 28(12):2896-900. 10. Yong R, et al. The durability of the Semmes-Weinstein 5.07 monofilament. J Foot Ankle Surg, 2000. 39(1):34-8. 11. McGill M, et al. Possible sources of discrepancies in the use of the Semmes-Weinstein monofilament. Impact on prevalence of insensate foot and workload requirements. Diabetes Care, 1999. 22(4):598-602. 12. Booth J, Young MJ. Differences in the performance of commercially available 10-g monofilaments. Diabetes Care, 2000. 23(7):984-8. Additional References 13. Armstrong DG, Lavery LA, Quebedeaux TL, Fleishli JG, Vela S: Choosing a Practical Screening Instrument to Identify Patients at Risk for Diabetic Foot Ulceration. Arch Int Med 158: 289-292, 1998. 14. Diamond JE, et al. Reliability of a diabetic foot evaluation. Phys Ther, 1989. 69(10):797-802. 15. Mueller MJ, et al. Insensitivity, limited joint mobility, and plantar ulcers in patients with diabetes mellitus. Phys Ther, 1989. 69(6):453-9; discussion 459-62.